Project Summary/Abstract Pancreas adenocarcinoma remains among the most lethal cancers with an expected 5-year survival of <5%. There are over to 45,000 new diagnoses each year and a similar number of deaths making it the fourth most common cause of cancer related mortality in the United States. Despite significant progress in breast cancer, colon cancer and melanoma, there has been no appreciable change in the mortality from pancreas cancer in the past four decades. Two factors that make pancreas cancer particularly difficult to treat are its relative proclivity towards early dissemination and its resistance to chemotherapy and radiation. One proposed mechanism that underlies both of these phenomena is epithelial to mesenchymal transition (EMT) in which pancreatic ductal cells gain the ability to shed their polarity and adhesive proteins and invade through surrounding stroma into blood vessels and lymphatics. We have identified elevated levels of the cytokine interleukin-22 (IL-22) in pre-invasive and invasive pancreas cancers and demonstrated its ability to increase transcription of genes that mediate EMT. We have also shown that IL-22 promotes invasion and proliferation of pancreatic tumor cells, in-vitro, and tumor engraftment and growth, in-vivo. In this proposal, we will determine how IL-22 leads to EMT in pancreas cancer cells and better determine its significance in cancer initiation and progression, in-vivo. We will also explore the role of innate lymphoid cells as the intra-tumoral source of IL-22 both in mice and humans. The overall goal of this application is to support my continued training and development to become an independent investigator in tumor immunology and pancreas cancer biology. The career development plan is based on formal didactic coursework, experiential learning and mentored basic science training. I have received generous support and protected time from my department and will work closely with my mentor Dr. Weiping Zou, MD, PhD, a respected and experienced tumor immunologist. I have also constructed a mentorship committee, each of whom has expertise in immunology and/or pancreas cancer biology and is tasked with furthering my development as a researcher and helping complete this project. My main research goals are to determine the mechanisms by which IL-22 leads to EMT and determine its biologic significance in an autochthonous pancreas cancer murine model. The major themes of the my research interests are reflected in the Specific Aims of this proposal: (1) To determine how IL-22 signaling in pancreas cells leads to EMT, (2) to determine the effect of IL-22 signaling on pancreas cancer initiation, progression and metastasis in a genetically engineered mouse model of pancreas adenocarcinoma, and (3) to identify the predominant source of IL-22 in pancreas tumors in both humans and mice. Successful completion of these studies should increase our understanding of the role of innate inflammation in pancreas cancer initiation and progression and provide new immunotherapeutic targets for this difficult to treat malignancy.